Antibodies with Altered Binding to FcRn and Methods of Using Same

Abstract

This invention relates to antibodies with altered binding to FcRn, and particularly antibodies having enhanced binding to FcRn and/or enhanced serum half-lives. The invention also relates to methods of using the antibodies and compositions comprising them in the diagnosis, prognosis and therapy of diseases such as cancer, autoimmune diseases, inflammatory disorders, and infectious disease.

1 - 19 . (canceled) 
     
     
         20 . A method of enhancing neonatal Fc receptor (FcRn) activity in a subject, said method comprising administering to said subject a polypeptide comprising a variant human IgG Fc region, wherein said variant human IgG Fc region:
 (A) contains a CH2 domain and a CH3 domain; and   (B) possesses an amino acid sequence that differs from the amino acid sequence of a wild-type Fc region by comprising an aspartic acid at position 288 and a lysine at position 435, wherein the positions are numbered according to the EU index as in Kabat.   
     
     
         21 . The method of  claim 20 , wherein said variant human IgG Fc region is a variant human IgG1 Fc region. 
     
     
         22 . The method of  claim 20 , wherein said polypeptide is an antibody, a single chain antibody or a diabody. 
     
     
         23 . The method of  claim 20 , further comprising the administration of an additional therapeutic agent in combination with said polypeptide. 
     
     
         24 . The method of  claim 23 , wherein said therapeutic agent is selected from the group consisting of a radiation therapeutic agent, a hormonal therapeutic agent, an immunotherapeutic agent, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an anti-neoplastic agent, an anti-bacterial agent, an anti-fungal agent, an anti-protozoan agent, and an anti-viral agent. 
     
     
         25 . The method of  claim 20 , wherein said subject is human. 
     
     
         26 . The method of  claim 20 , wherein said polypeptide binds a tumor antigen or a pathogen-related antigen. 
     
     
         27 . The method of  claim 26 , wherein said tumor antigen is selected from the group consisting of 17-1A, αvβ3, AFP, BCR complex, CA125, CD3, CD18, CD20, CD22, CD33, CD44, CD52, CEA, CTLA-4, DNA-associated proteins, EGF receptor, Ep-CAM, GD2-ganglioside, gp IIIb/IIIa, gp72, HER2/neu, HLA-DR 10 beta, HLA-DR antigen, IgE, ganglioside GD3, MUC-1, nuC242, PEM antigen, SK-1 antigen, tumor antigen CA125, tumor antigen MUC1, VEGF, and VEGF-receptor. 
     
     
         28 . The method of  claim 26 , wherein said pathogen-related antigen is selected from the group consisting of a smallpox antigen, a West Nile Virus antigen, an anthrax antigen, a bacterial meningitis antigen, a cholera antigen, a  Clostridium difficile  antigen, a Lyme disease antigen, a  Pateurella pestis  antigen, a  pneumococcal  antigen, a  streptococcal  antigen, a  Clostridium tetani  antigen, a micrococcal antigen, and a tularemia antigen. 
     
     
         29 . The method of  claim 20 , wherein said variant human IgG Fc region exhibits enhanced binding affinity to FcRn at least 2-fold greater than that of said wild-type Fc region. 
     
     
         30 . The method of  claim 20 , wherein said polypeptide comprising said variant human IgG Fc region exhibits enhanced serum half-life relative to a comparable molecule comprising said wild-type Fc region. 
     
     
         31 . A method of increasing serum half-life of a polypeptide comprising a human IgG Fc region, comprising modifying said human IgG Fc region to comprise amino acid modifications relative to a wild-type human IgG Fc region to yield a variant human IgG Fc region, wherein said variant human IgG Fc region:
 (A) contains a CH2 domain and a CH3 domain;   (B) possesses an amino acid sequence that differs from the amino acid sequence of said wild-type human IgG Fc region by comprising an aspartic acid at position 288 and a lysine at position 435, wherein the positions are numbered according to the EU index as in Kabat; and   (C) binds to neonatal Fc receptor (FcRn) with an increased affinity relative to that of said wild-type human IgG Fc region.   
     
     
         32 . The method of  claim 31 , wherein said variant human IgG Fc region is a variant human IgG1 Fc region. 
     
     
         33 . The method of  claim 31 , wherein said polypeptide is an antibody, a single chain antibody or a diabody. 
     
     
         34 . The method of  claim 31 , wherein said polypeptide binds a tumor antigen or a pathogen-related antigen. 
     
     
         35 . A polypeptide having a variant human IgG Fc region, wherein said variant human IgG Fc region:
 (A) contains a CH2 domain and a CH3 domain;   (B) possesses an amino acid sequence that differs from the amino acid sequence of a wild-type human IgG Fc region by comprising an aspartic acid at position 288 and a lysine at position 435, wherein the positions are numbered according to the EU index as in Kabat; and   (C) bind to neonatal Fc receptor (FcRn) with an increased affinity relative to that of said wild-type human IgG Fc region.   
     
     
         36 . The polypeptide of  claim 35 , wherein said polypeptide is an antibody, a single chain antibody or a diabody. 
     
     
         37 . The polypeptide of  claim 35 , wherein said variant human IgG Fc region is a variant human IgG1, IgG2, IgG3 or IgG4 Fc region. 
     
     
         38 . A pharmaceutical composition comprising the polypeptide of  claim 35 , and a pharmaceutically acceptable carrier. 
     
     
         39 . The pharmaceutical composition of  claim 38 , further comprising an additional therapeutic agent. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein said additional therapeutic agent is selected from the group consisting of a radiation therapeutic agent, a hormonal therapeutic agent, an immunotherapeutic agent, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an anti-neoplastic agent, an anti-bacterial agent, an anti-fungal agent, an anti-protozoan agent, and an anti-viral agent.